High blood or plasma cholesterol levels or hypercholesterolemia represent a common disease pattern preliminary in the well situated countries of the western hemisphere. Cholesterol may cause a “hardening of the arteries” so that arteries become narrowed and blood flow to the heart is slowed down or even blocked with the consequence that provision of oxygen to the organs is constrained. Hypercholesterolemia has been implicated in atherosclerosis, heart attack, and stroke and is one of several conditions that may lead to coronary artery disease, which is the leading cause of death in the United States, accounting for approximately 600,000 deaths per year. The risk group includes the overweight, smokers, those with a poor diet (e.g. one rich in saturated fats), those who take inadequate exercise and suffering from stress. For such risk individuals, as well as those tested and found to have unduly high plasma cholesterol levels, a variety of treatments have been proposed, e.g. changes in diet and habits, increased exercise, etc. However, such treatments are not always easy to enforce and there exist a need for improved medicinal treatments which are effective at reducing plasma cholesterol levels.
In above mentioned cases, ezetimibe can be prescribed, since it is indicated mainly for primary hypercholesterolemia (administered alone or in combination with an HMG-CoA reductase inhibitor), homozygous familial hypercholesterolemia (administered with atorvastatin or simvastatin) and homozygous sitosterolemia [PDR prescribing information for Zetia®]. Ezetimibe is sold under the brand name Zetia®, which is marketed by Merck/Schering-Plough Pharmaceuticals. Zetia® is available as a tablet for oral administration containing 10 mg of ezetimibe. The inactive ingredients of Zetia® are reported to be croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The recommended dose is 10 mg once daily, administered with or without food according to the Zetia® label.
Ezetimibe, a white crystalline powder disclosed in EP 0 720 599, is reported to be freely to very soluble in ethanol, methanol, and acetone, and practically insoluble in water. Further it is reported to have a melting point of about 163° C. and to be stable at ambient temperature. The mechanism of action of ezetimibe on absorption and resorption inhibition of cholesterol involves increased excretions of cholesterol and its intestinally generated metabolites with the faeces. This effect results in lowered body cholesterol levels, increased cholesterol synthesis, and decreased triglyceride synthesis. The increased cholesterol synthesis initially provides for the maintenance of cholesterol levels in the circulation, levels that eventually decline as the inhibition of cholesterol absorption and resorption continues. The overall effect of drug action is the lowering of cholesterol levels in the circulation and tissues of the body.
Other commonly used compounds for the treatment or prevention of high cholesterol levels in individuals are the statins, such as fluvastatin, simvastatin, and lovastatin. Among the group of statins, particularly simvastatin exhibited good results in the treatment of conditions characterized by high cholesterol levels. Methods for its preparation are disclosed in e.g. in EP 0 033 538, EP 0 351 918, and EP 0 299 656. Simvastatin exerts a cholesterol reducing effect by inhibiting the conversion of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) to mevalonate, an early step in the biosynthetic pathway of cholesterol. Additionally, simvastatin reduces the amount of very-low density lipoproteins (VLDL) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) and is thus capable to counteract diseases like atherosclerosis. Simvastatin is marketed worldwide and sold under the trade name ZOCOR®. ZOCOR® tablets contain simvastatin, anhydrous lactose, microcrystalline cellulose (fillers), pregelatinized maize starch (disintegrant), magnesium stearate (lubricant), butylated hydroxyanisol (BHA), citric acid monohydrate and ascorbic acid (antioxidants).
In order to provide improved medication combination products, such as a combination of ezetimibe and simvastatin, were considered. Such a combination is marketed, for example, in the USA under the trade name VYTORIN®. The commercially available VYTORIN® tablets contain ezetimibe, simvastatin, lactose monohydrate, microcrystalline cellulose (fillers), hydroxylpropyl methylcellulose (binder), croscarmellose sodium (disintegrant), magnesium stearate (lubricant), butylated hydroxyanisol (BHA), citric acid monohydrate and propyl gallate (antioxidants). For the time being, combinations comprising 10 mg of ezetimibe each and 10, 20, 40 and 80 mg simvastatin, respectively, are commercially available. Such a combination medicament has been proven to be effective in the treatment and/or prevention of atherosclerosis and related conditions.
When a solid dosage form with a poorly soluble drug (e.g. ezetimibe) is taken orally, the drug must dissolve in aqueous gastrointestinal fluids in, e.g., patient's stomach, before it can exert a therapeutic effect. A recurring problem with solid oral dosage forms comprising poorly water soluble drugs (e.g. ezetimibe) is that the rate of dissolution of the drug limits its biological availability.
Known methods for preparing formulations containing ezetimibe mostly use wet granulation, which is the method of choice for the preparation of ezetimibe/simvastatin combinations.
EP 1 849 459 discloses compositions containing ezetimibe with improved solubility of ezetimibe and increased bioavailability, methods of their preparation, and method of treatment using the same. An ezetimibe composition according to this document may be prepared, for example, by co-milling ezetimibe with at least one hydrophilic excipient.
WO 2008/101723 discloses a pharmaceutical composition comprising at least one cholesterol absorption inhibitor such as ezetimibe with improved dissolution rate and exhibiting a high bioavailability in amorphous form and at least one hydrophilic polymer. In one embodiment, the amorphous cholesterol absorption inhibitor is finely dispersed in the hydrophilic polymer by means of spray-drying.
WO 2006/134604 describes stable antihyperlipoproteinemic combinations of solid oral pharmaceutical formulations containing ezetimibe, HMG-CoA reductase inhibitor, disintegrants and glidants. During manufacture, a milling step in order to achieve the desired particle size distribution is carried out. However, in such milling steps often agglomerates of the particles are formed. This can negatively influence the properties of the formulations.
WO 2007/003365 describes stable pharmaceutical compositions containing simvastatin and/or ezetimibe and their preparation. Some embodiments disclose the mixing of a part of the ingredients in a high shear mixer and granulation, followed by a drying- and sieving-step of the obtained granules.
U.S. Pat. No. 7,229,982 B2 discloses a pharmaceutical composition comprised of a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor, one or more anti-oxidants, microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate and lactose.
However, despite the above described methods and preparations of formulations containing ezetimibe, there is a need for an improved process for the preparation of a dosage form containing ezetimibe, in particular with regard to a dissolution profile that allows for a good effectivity and with regard to an improved processability.